{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,28]],"date-time":"2025-10-28T00:27:26Z","timestamp":1761611246316},"reference-count":35,"publisher":"Oxford University Press (OUP)","issue":"19","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2009,10,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Motivation: Diverse studies have shown that correlated mutation (CM) is an important molecular evolutionary process alongside conservation. However, attempts to find the residue pairs that co-evolve under the structural and\/or functional constraints are complicated by the fact that a large portion of covariance signals found in multiple sequence alignments arise from correlations due to common ancestry and stochastic noise.<\/jats:p>\n               <jats:p>Results: Assuming that the background noise can be estimated from the coevolutionary relationships among residues, we propose a new measure for background noise called the normalized coevolutionary pattern similarity (NCPS) score. By subtracting NCPS scores from raw CM scores and combining the results with an entropy factor, we show that these new scores effectively reduce the background noise. To test the effectiveness of this method in detecting residue pairs coevolving under the structural constraints, two independent test sets were performed, showing that this new method performs better than the most accurate method currently available. In addition, we also applied our method to double mutant cycle experiments and protein\u2013protein interactions. Although more rigorous tests are required, we obtained promising results that our method tended to explain those data better than other methods. These results suggest that the new noise-reduced CM scores developed in this study can be a valuable tool for the study of correlated mutations under the structural and\/or functional constraints in proteins.<\/jats:p>\n               <jats:p>Contact: \u00a0kds@kaist.ac.kr<\/jats:p>\n               <jats:p>Availability: \u00a0http:\/\/pbil.kaist.ac.kr<\/jats:p>\n               <jats:p>Supplementary information: \u00a0Supplementary data are available at Bioinformatics online.<\/jats:p>","DOI":"10.1093\/bioinformatics\/btp455","type":"journal-article","created":{"date-parts":[[2009,7,24]],"date-time":"2009-07-24T00:55:41Z","timestamp":1248396941000},"page":"2506-2513","source":"Crossref","is-referenced-by-count":32,"title":["A new method for revealing correlated mutations under the structural and functional constraints in proteins"],"prefix":"10.1093","volume":"25","author":[{"given":"Byung-Chul","family":"Lee","sequence":"first","affiliation":[{"name":"Department of Bio and Brain Engineering, KAIST, Daejeon 305-701, Korea"}]},{"given":"Dongsup","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Bio and Brain Engineering, KAIST, Daejeon 305-701, Korea"}]}],"member":"286","published-online":{"date-parts":[[2009,7,23]]},"reference":[{"key":"2023013112125134300_B1","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1016\/0022-2836(87)90352-4","article-title":"Correlation of co-ordinated amino acid substitutions with function in viruses related to tobacco mosaic virus","volume":"193","author":"Altschuh","year":"1987","journal-title":"J. Mol. Biol."},{"key":"2023013112125134300_B2","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1002\/prot.22168","article-title":"Optimal data collection for correlated mutation analysis","volume":"74","author":"Ashkenazy","year":"2009","journal-title":"Proteins"},{"key":"2023013112125134300_B3","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1093\/oxfordjournals.molbev.a026229","article-title":"Correlations among amino acid sites in bhlh protein domains: an information theoretic analysis","volume":"17","author":"Atchley","year":"2000","journal-title":"Mol. Biol. Evol."},{"key":"2023013112125134300_B4","doi-asserted-by":"crossref","first-page":"14004","DOI":"10.1021\/bi011268l","article-title":"Energetics of side chain packing in staphylococcal nuclease assessed by systematic double mutant cycles","volume":"40","author":"Chen","year":"2001","journal-title":"Biochemistry"},{"key":"2023013112125134300_B5","doi-asserted-by":"crossref","first-page":"4679","DOI":"10.1073\/pnas.0711732105","article-title":"Reassessing a sparse energetic network within a single protein domain","volume":"105","author":"Chi","year":"2008","journal-title":"Proc. Natl Acad. Sci. US A"},{"key":"2023013112125134300_B6","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1177\/117693430800400003","article-title":"Why Should We Care About Molecular Coevolution?","volume":"4","author":"Codoner","year":"2008","journal-title":"Evol. Bioinform."},{"key":"2023013112125134300_B7","doi-asserted-by":"crossref","first-page":"1565","DOI":"10.1093\/bioinformatics\/bth128","article-title":"A perturbation-based method for calculating explicit likelihood of evolutionary co-variance in multiple sequence alignments","volume":"20","author":"Dekker","year":"2004","journal-title":"Bioinformatics"},{"key":"2023013112125134300_B8","doi-asserted-by":"crossref","first-page":"2120","DOI":"10.1110\/ps.062249106","article-title":"Residue centrality, functionally important residues, and active site shape: analysis of enzyme and non-enzyme families","volume":"15","author":"del Sol","year":"2006","journal-title":"Protein Sci."},{"key":"2023013112125134300_B9","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1093\/bioinformatics\/btm604","article-title":"Mutual information without the influence of phylogeny or entropy dramatically improves residue contact prediction","volume":"24","author":"Dunn","year":"2008","journal-title":"Bioinformatics"},{"key":"2023013112125134300_B10","doi-asserted-by":"crossref","first-page":"835","DOI":"10.1093\/protein\/14.11.835","article-title":"Prediction of contact maps with neural networks and correlated mutations","volume":"14","author":"Fariselli","year":"2001","journal-title":"Protein Engineering"},{"key":"2023013112125134300_B11","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1002\/prot.1173","article-title":"Progress in predicting inter-residue contacts of proteins with neural networks and correlated mutations","volume":"45","author":"Fariselli","year":"2001","journal-title":"Prot Struct Funct Genet"},{"key":"2023013112125134300_B12","doi-asserted-by":"crossref","first-page":"579","DOI":"10.1007\/BF00486096","article-title":"An improved method for determining codon variability in a gene and its application to the rate of fixation of mutations in evolution","volume":"4","author":"Fitch","year":"1970","journal-title":"Biochem. Genet."},{"key":"2023013112125134300_B13","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1002\/prot.20098","article-title":"Influence of conservation on calculations of amino acid covariance in multiple sequence alignments","volume":"56","author":"Fodor","year":"2004","journal-title":"Proteins"},{"key":"2023013112125134300_B14","doi-asserted-by":"crossref","first-page":"7156","DOI":"10.1021\/bi050293e","article-title":"Mutual information in protein multiple sequence alignments reveals two classes of coevolving positions","volume":"44","author":"Gloor","year":"2005","journal-title":"Biochemistry"},{"key":"2023013112125134300_B15","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1002\/prot.340180402","article-title":"Correlated mutations and residue contacts in proteins","volume":"18","author":"G\u00f6bel","year":"1994","journal-title":"Proteins"},{"key":"2023013112125134300_B16","volume-title":"Fundamentals of Molecular Evolution.","author":"Graur","year":"2000","edition":"2"},{"key":"2023013112125134300_B17","doi-asserted-by":"crossref","first-page":"832","DOI":"10.1002\/prot.20933","article-title":"Correlated mutations: advances and limitations. A study on fusion proteins and on the Cohesin-Dockerin families","volume":"63","author":"Halperin","year":"2006","journal-title":"Proteins Struct. Funct. Bioinform."},{"key":"2023013112125134300_B18","doi-asserted-by":"crossref","first-page":"915","DOI":"10.1002\/prot.21620","article-title":"New insight into long-range nonadditivity within protein double-mutant cycles","volume":"70","author":"Istomin","year":"2008","journal-title":"Proteins Struct. Funct. Bioinform."},{"key":"2023013112125134300_B19","doi-asserted-by":"crossref","first-page":"863","DOI":"10.1002\/prot.21972","article-title":"Analysis of the residue-residue coevolution network and the functionally important residues in proteins","volume":"72","author":"Lee","year":"2008","journal-title":"Proteins Struct. Funct. Bioinform."},{"key":"2023013112125134300_B20","doi-asserted-by":"crossref","first-page":"438","DOI":"10.1126\/science.1159052","article-title":"Surface sites for engineering allosteric control in proteins","volume":"322","author":"Lee","year":"2008","journal-title":"Science"},{"key":"2023013112125134300_B21","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1093\/bioinformatics\/17.3.282","article-title":"Clustering of highly homologous sequences to reduce the size of large protein databases","volume":"17","author":"Li","year":"2001","journal-title":"Bioinformatics"},{"key":"2023013112125134300_B22","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1093\/bioinformatics\/18.1.77","article-title":"Tolerating some redundancy significantly speeds up clustering of large protein databases","volume":"18","author":"Li","year":"2002","journal-title":"Bioinformatics"},{"key":"2023013112125134300_B23","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1126\/science.286.5438.295","article-title":"Evolutionarily conserved pathways of energetic connectivity in protein families","volume":"286","author":"Lockless","year":"1999","journal-title":"Science"},{"key":"2023013112125134300_B24","doi-asserted-by":"crossref","first-page":"D192","DOI":"10.1093\/nar\/gki069","article-title":"CDD: a conserved domain database for protein classification","volume":"33","author":"Marchler-Bauer","year":"2005","journal-title":"Nucleic Acids Res."},{"key":"2023013112125134300_B25","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1073\/pnas.91.1.98","article-title":"How frequent are correlated changes in families of protein sequences?","volume":"91","author":"Neher","year":"1994","journal-title":"Proc. Natl Acad. Sci. US A"},{"key":"2023013112125134300_B26","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1093\/protein\/gzi029","article-title":"Detection and reduction of evolutionary noise in correlated mutation analysis","volume":"18","author":"Noivirt","year":"2005","journal-title":"Prot Eng Des Sel"},{"key":"2023013112125134300_B27","doi-asserted-by":"crossref","first-page":"647","DOI":"10.1093\/protein\/10.6.647","article-title":"Effectiveness of correlation analysis in identifying protein residues undergoing correlated evolution","volume":"10","author":"Pollock","year":"1997","journal-title":"Protein Eng."},{"key":"2023013112125134300_B28","doi-asserted-by":"crossref","first-page":"579","DOI":"10.1038\/nature03990","article-title":"Natural-like function in artificial WW domains","volume":"437","author":"Russ","year":"2005","journal-title":"Nature"},{"key":"2023013112125134300_B29","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1093\/protein\/7.3.349","article-title":"Can three-dimensional contacts in protein structures be predicted by analysis of correlated mutations?","volume":"7","author":"Shindyalov","year":"1994","journal-title":"Protein Eng."},{"key":"2023013112125134300_B30","doi-asserted-by":"crossref","first-page":"1043","DOI":"10.1016\/j.cell.2008.04.040","article-title":"Rewiring the specificity of two-component signal transduction systems","volume":"133","author":"Skerker","year":"2008","journal-title":"Cell"},{"key":"2023013112125134300_B31","doi-asserted-by":"crossref","first-page":"512","DOI":"10.1038\/nature03991","article-title":"Evolutionary information for specifying a protein fold","volume":"437","author":"Socolich","year":"2005","journal-title":"Nature"},{"key":"2023013112125134300_B32","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1038\/nsb881","article-title":"Evolutionarily conserved networks of residues mediate allosteric communication in proteins","volume":"10","author":"Suel","year":"2003","journal-title":"Nat. Struct. Biol."},{"key":"2023013112125134300_B33","doi-asserted-by":"crossref","first-page":"4673","DOI":"10.1093\/nar\/22.22.4673","article-title":"Clustal-W \u2013 improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice","volume":"22","author":"Thompson","year":"1994","journal-title":"Nucleic Acids Res."},{"key":"2023013112125134300_B34","doi-asserted-by":"crossref","first-page":"750","DOI":"10.1093\/bioinformatics\/btg072","article-title":"Using multiple interdependency to separate functional from phylogenetic correlations in protein alignments","volume":"19","author":"Tillier","year":"2003","journal-title":"Bioinformatics"},{"key":"2023013112125134300_B35","doi-asserted-by":"crossref","first-page":"3288","DOI":"10.1073\/pnas.97.7.3288","article-title":"Separation of phylogenetic and functional associations in biological sequences by using the parametric bootstrap","volume":"97","author":"Wollenberg","year":"2000","journal-title":"Proc. Natl Acad. Sci. USA"}],"container-title":["Bioinformatics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/25\/19\/2506\/48995709\/bioinformatics_25_19_2506.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/25\/19\/2506\/48995709\/bioinformatics_25_19_2506.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,31]],"date-time":"2023-01-31T21:39:40Z","timestamp":1675201180000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article\/25\/19\/2506\/181040"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2009,7,23]]},"references-count":35,"journal-issue":{"issue":"19","published-print":{"date-parts":[[2009,10,1]]}},"URL":"https:\/\/doi.org\/10.1093\/bioinformatics\/btp455","relation":{},"ISSN":["1367-4811","1367-4803"],"issn-type":[{"value":"1367-4811","type":"electronic"},{"value":"1367-4803","type":"print"}],"subject":[],"published-other":{"date-parts":[[2009,10,1]]},"published":{"date-parts":[[2009,7,23]]}}}